High impulsivity predicts the switch to compulsive cocaine-taking

Abstract

Both impulsivity and novelty-seeking have been suggested to be behavioral markers of the propensity to take addictive drugs. However, their relevance for the vulnerability to compulsively seek and take drugs, which is a hallmark feature of addiction, is unknown. We report here that, whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration, high impulsivity predicts the development of addiction-like behavior in rats, including persistent or compulsive drug-taking in the face of aversive outcomes. This study shows experimental evidence that a shift from impulsivity to compulsivity occurs during the development of addictive behavior, which provides insights into the genesis and neural mechanisms of drug addiction.

Fig. 1. Impulsivity and novelty-induced locomotor activity: two distinct phenotypes

A-B. During long ITI sessions in the 5-CSRTT, HI rats showed more premature responses than LI rats [Group: F_3,36 = 14.4, p < 0.01, Schedule: F_8,288 = 130.22, p < 0.01, Schedule × Group: F_{24, 288} = 7.01, p < 0.01] (***: p < 0.001) (A) and HR (p < 0.01) or LR rats (p < 0.05) (B). HR rats did not differ from LR rats nor from LI subjects (B). C-D. HR rats were more reactive to novelty than LR rats [first 30 min (left histogram) or total duration of the session (right histogram): Group: F_3,35 = 12.17, p < 0.01, F_3,35 = 17.63, p < 0.01, respectively, Group × Time: F_6,70 = 1.26, ns and F_30,350 < 1, respectively], (p < 0.001). HI and LI subjects differed from both HR (p < 0.01) and LR rats (# p < 0.01) but never from each other. * versus HR, p < 0.05, ** p < 0.01, *** p < 0.01. Black and grey dotted lines represent the average premature responses during the last two long inter-trial intervals for HI and LI rats, respectively.

Fig. 2. Novelty-induced locomotor activity predicts the propensity to acquire cocaine SA

A. HR rats showed an upward shift of the cocaine dose-response curve compared to LR littermates [Group: F_{1, 16} = 4.9, p < 0.05, Dose: F_{6, 96} = 11.73, p < 0.01, and Group × Dose: F_{6, 96} = 4.39, p < 0.01], HR rats infusing more cocaine at the lowest three doses than vehicle (p < 0.01). B. HI and LI subjects did not differ in their number of cocaine infusions self-administered [Group: F_1,16 < 1, Dose: F_{6, 96} = 10.79, p < 0.01, Group × Dose: F_{6, 96}<1].

Fig. 3. Highly impulsive rats closely resemble 3 criteria rats

After protracted self-administration 0, 1, 2 or 3 criteria rats were identified. A. When ranked on a linear addiction scale [R² = 0.99, Group: F_3,19 = 34.43, p < 0.01], 3 criteria rats had addiction scores (2.8 ± 0.6) above the standard deviation (2.1), and higher than all the other groups (vs 0 and 1 criteria rats: ¤ p < 0.01, vs 2 criteria rats: # p ≤ 0.05). B. HI rats displayed higher addiction scores than LI rats [F_1,9 = 7.55, p < 0.05: *] whereas HR did not differ from LR rats. Only HI rats did not differ from 3 criteria rats for their addiction score [F_5,30 = 10.13, p < 0.01], displaying higher addiction scores than 0 criteria (p < 0.01), and HR rats (p < 0.05). HR, LR and LI rats did not differ from 0 criteria rats.

Fig. 4. Impulsivity predicts the transition to compulsivity

HI rats (n = 5) displayed higher resistance to punishment than LI rats (n = 6) [F_{1, 9} = 12.79, p < 0.01] whereas HR (n = 5) rats did not differ from LR rats (n = 5). When compared to 0 and 3 criteria rats for their resistance to punishment [Group: F_5,30 = 10.13, p < 0.01], only HI rats were similar to 3 criteria rats, showing greater resistance to punishment than 0 criteria, LI and HR rats (p < 0.05). LI and HR rats differed from 3 criteria but not from 0 criteria rats (A). **p < 0.01. B. Impulsivity predicts compulsive cocaine self-administration (R=0.42, p<0.05). Grey and black shadings represent LI and HI rats, respectively.